1. Field of the Invention
The present invention relates generally to the fields of molecular genetics and diagnosis of genetic diseases. More specifically, the present invention relates to a large scale genotyping of diseases and diagnostic tests and kits for same.
2. Description of the Related Art
Expansion of repeat sequences involving the trinucleotides CAG, CTG, CGG or GAA has been shown to be the primary cause of several neurological disorders.sup.1. Among them, CAG repeat expansions have been associated with a group of neurodegenerative disorders including Huntington disease.sup.2, spinobulbar muscular atrophy.sup.3, spinocerebellar ataxia type 1 (SCA1).sup.4, spinocerebellar ataxia type 2 (SCA2).sup.5-7, spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD).sup.8, and dentatorubral-pallidoluysian atrophy/Haw-River syndrome.sup.9. All these disorders are progressive diseases leading to degeneration of the neurons in central nervous system. The CAG repeats in the respective genes show length polymorphism in the human population, typically, not exceeding 40 repeats. In affected individuals, the expanded alleles contain 36-121 repeats.sup.10.
CAG repeat expansions are much smaller than t h e hundreds or thousands of repeats often seen in diseases with CGG, CTG, and GAA expansions.sup.11-14. The expanded CAG alleles show variable degrees of instability in both germline and somatic tissuesl.sup.15,16. Intergenerational changes of the CAG repeat size are often biased toward further expansion, particularly if paternally transmitted, providing the molecular basis for anticipation. The CAG repeat arrays in these diseases are located in the coding regions of the involved genes and are translated into polyglutamine tracts in the protein products.sup.17. It has been postulated that an expansion of the polyglutamine tract produces a gain of function in the protein product in each disease accounting for the dominant inheritance. Based on the relatively uniform characteristics of diseases caused by CAG repeat expansions, it has been speculated that other neurodegenerative diseases with similar clinical characteristics may have expansions of CAG repeats. Indeed, a study by Trottier and colleagues demonstrated that an antibody against a polyglutamine tract detects abnormally large proteins in tissues from patients with either SCA2 or spinocerebellar ataxia type 7 (SCA7), suggesting that the mutation responsible for SCA2 and SCA7 is an expansion of a polyglutamine repeat tract.sup.18.
The prior art is deficient in the lack of effective means for the large scale genotyping of genetic diseases and diagnostic tests and kits for diagnosing such diseases. The present invention fulfills this long-standing need and desire in the art.